About 75% of children with acute lymphoblastic leukemia (ALL) can be cured by using current therapies. Despite increasing dose intensity, cure rates have reached a plateau, and late sequelae of treatment exist for many children. Improved outcome must originate from laboratory investigations of the biology of ALL and decreasing the harmful effects of treatment. Over the past fifteen years the investigators in this Program Project have collaborated on studies to maximize therapeutic intensity in children with newly diagnosed ALL. These efforts resulted in significant improvements in event-free survival. We have also developed autologous bone marrow transplantation for relapsed ALL. We now propose to continue collaboration between laboratory and clinical scientists to develop the most effective, least toxic therapies, balancing the quality of life against the rate of cure to maximize the therapeutic ratio in newly diagnosed patients. In both newly diagnosed patients and in relapsed patients undergoing autologous transplantation, we will determine the clinical significance of minimal residual leukemia. We will explore apoptosis, a critical mechanism of tumor cell killing, and its relationship to the p53 gene metabolic pathway. These investigations may provide a scientific basis for optimizing clinical treatments, both to decrease toxicity and improve efficacy in refractory patients. We will continue ongoing studies of the cardiotoxicity of doxorubicin, including the cardioprotective effect of ADR 529, and the value of serial cardiac measurements in predicting the late toxicity of bolus versus continuous infusion of doxorubicin. We also will determine the most efficacious and least toxic combination of radiotherapy and intrathecal drug for prevention of central nervous system leukemia in ongoing studies of neuropsychological and growth toxicities of central nervous system therapy. Because recurrent leukemia is a major cause of relapse and subsequent death, we will develop laboratory-based, novel, non-overlapping treatment strategies which can be added to current treatment approaches to eradicate residual leukemia. By translating basic laboratory observations to clinical trials, we desire to improve outcome and decrease toxicity for children with ALL.